The development of new capillary blood vessels, also known as angiogenesis, occurs in normal bodily processes such as healing of wounds, growth of organs such as the corpus luteum, and growth of the embryo. Angiogenesis is also a characteristic that links many diverse diseases. See Maugh II, Science 212: 1374-1375 (1981); Auerback, Lymphokines 4: 69-68 (1981). It is a major component of some ophthalmological pathologies such as corneal graft rejection, corneal neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma, Garner, Int. Rev. Exp. Pathol 28: 249-307 (1986), and is also a major factor in many ulcerative diseases such as rheumatoid arthritis, ulcerative colitis, and gastric ulcer. In addition, angiogenesis is a major component in pathological but nonmalignant conditions such as hemangioma, angiofibroma of the nasopharynx, avascular necrosis of bone, and psoriasis, and is further an essential requirement for tumor growth and metastasis, See, e.g., Folkman, J. Natl. Cancer Inst. 82: 4-6 (1990); Weidner et al., New Engl. J. Med. 324: 1-8 (1991).
Although originally developed for their anti-inflammatory properties, glucocorticoids are now recognized to have a wide variety of therapeutic uses. For example, many steroids with anti-inflammatory activity inhibit angiogenesis. In particular, steroids possessing the glucocorticoid side chain have been shown to inhibit angiogenesis, both alone and in conjunction with heparin, heparin fragments, or water-soluble cyclodextrin sulphate salts. See, e.g., Folkman et al., U.S. Pat. No. 5,019,562 (1991); Braughler et al., U.S. Pat. No. 4,772,042 (1988); Folkman et al., Ann. Surg. 206: 374-3883 (1987).
A major drawback to the use of steroids having the glucocorticoid side chain and exhibiting anti-inflammatory activity lies in the side effects that accompany their use. The side effects include, among others, immunosuppression, iatrogenic Cushing syndrome, osteoporosis, gastric ulcer, and overt diabetes mellitus.
Oxidation of the dihydroxyacetone side chain of glucocorticoids produces androstane 17.beta.-carboxylic acids (etianic acids), which no longer possess anti-inflammatory activity, Bain et al., Journal Steroid Biochem. 5: 299 (1976); see also Monder et al., Journal Steroid Biochem 8: 897-908 (1977); Monder et al., Recent Prog. in Hormone Res. 36: 345-400 (1980), and which do not bind to the glucocorticoid receptor present in rat liver cytosol. Rousseau et al., Nature 279: 158-160 (1979). Conversion to their monoesters or 17.beta.-acyl derivatives leads to products with marginal anti-inflammatory activity. See Phillips et al., U.S. Pat. No. 3,856,828 (1974); Alvarez, U.S. Pat. No. 4,198,403 (1980). Such mono-esters and acyl derivatives have been reported to retain angiostatic activity. See Schreiber et al., U.S. Pat. No. 4,599,331 (1986).
In light of the foregoing, it is an object of the present invention to provide alternative methods for inhibiting angiogenesis.
It is also an object of the present invention to provide alternative methods for inhibiting angiogenesis which are not accompanied by glucocorticoid activity.
It is another object of the present invention to provide alternative methods of combatting tumors with steroids, and more particularly to provide such methods using steroids with reduced corticoidal side effects.
It is an additional object of the present invention to provide alternative methods for treating ophthalmologic conditions such as ocular hypertension and glaucoma through steroidal administration.
It is a further object to provide a method of reducing glucocorticoid activity through steroidal administration.